G. Multhoff et al., Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells, EXP HEMATOL, 27(11), 1999, pp. 1627-1636
We previously demonstrated that lysis of tumor cells that express Hsp70, th
e highly stress-inducible member of the HSP70 family, on their plasma membr
ane is mediated by natural killer (NK) cells. Here, we studied the effects
of different proteins of the HSP70 family in combination with interleukin 2
(IL-2) on the proliferation and cytotoxic activity of human NK cells in vi
tro. Proliferation of NK cells was significantly enhanced by human recombin
ant Hsp70 (rHsp70) and to a lesser extent by rHsp70homC, the recombinant C-
terminal peptide-binding domain derived from Hsp70hom, but not by the const
itutive Hsc70 or DnaK, the Escherichia coli analogue of human Hsp70. Even r
Hsp70 protein alone moderately enhances proliferation and cytolytic activit
y of NK cells, thus indicating that the stimulatory effect is not strictly
dependent on IL-2, NK cells stimulated with rHsp70 protein also exhibit an
increased secretion of interferon gamma (IFN-gamma), The phenotypic charact
erization of NK cells with specificity for Hsp70-expressing tumor cells rev
ealed a CD16(dim)/CD56(bright) and increased CD57 and CD94 expression. The
cytolytic activity of NK cells also was significantly reduced when a CD94-s
pecific antibody or rHsp70 was added directly before the cytotoxicity assay
, whereas other antibodies directed against CD57 and major histocompatibili
ty complex class I molecules or Hsp70 proteins, including Hsc70 and DnaK, d
id not affect the NK-mediated killing. However, long-term incubation of NK
cells with rHsp70 protein enhances not only the proliferative but also the
cytolytic response against Hsp70-expressing tumor cells, Our results indica
te that the C-terminal domain of Hsp70 protein affects not only the prolife
rative but also the cytolytic activity of a phenotypically distinct NK cell
population with specificity for Hsp70 expressing tumor cells. (C) 1999 Int
ernational Society for Experimental Hematology. Published by Elsevier Scien
ce Inc.